CN116194160A

CN116194160A - Tissue adhesive for use in a method of treatment for implanting an ophthalmic implant in a human or animal patient, and ophthalmic implant system

Info

Publication number: CN116194160A
Application number: CN202180063879.2A
Authority: CN
Inventors: A·沃尔夫斯坦
Original assignee: Carl Zeiss Meditec AG
Current assignee: Carl Zeiss Meditec AG
Priority date: 2020-09-18
Filing date: 2021-09-10
Publication date: 2023-05-30
Also published as: EP4213899A1; US20230218796A1; DE102020124372A1; WO2022058247A1

Abstract

The invention relates to a tissue adhesive (14) for use in a method of treatment in which an ophthalmic implant (12) is implanted in a human or animal patient and the ophthalmic implant (12) is at least partially connected to the eye tissue of the patient in an integrally bonded manner by means of the tissue adhesive (14). The invention also relates to an ophthalmic implant system (10) comprising: an ophthalmic implant (12) for implantation in a human or animal eye, and a tissue adhesive (14) by means of which the ophthalmic implant (12) is at least partially connectable to the eye tissue of the patient in an integrally bonded manner.

Description

Tissue adhesive for use in a method of treatment for implanting an ophthalmic implant in a human or animal patient, and ophthalmic implant system

Technical Field

The present invention relates to a tissue adhesive for use in a method of treatment for implanting an ophthalmic implant in a human or animal patient, and to an ophthalmic implant system for such a method of treatment.

Background

In the case of ophthalmic implants such as intraocular lenses (IOLs) or artificial capsular bags, the interaction between the implant and adjacent biological tissue means that a number of complications may occur. For example, in some cases, so-called Posterior Capsular Opacification (PCO), secondary cataract, occurs after cataract surgery. PCO is post-operative capsular opacification after surgical removal of the natural lens. The remaining lens epithelial cells (E cells) in the equatorial region of the capsular bag have mitotic activity and can be transformed into fibroblasts. These then trigger a wound healing involving the formation of connective tissue containing collagen. Since some fibroblast subtypes not only migrate to the inside of the capsular bag, but also shrink, folds are formed in the capsular bag. Thus, capsular opacification is a result of the wound healing process and associated scarring. This is known as "secondary cataract" or "secondary cataract" because the resulting clouding of the lens is responsible for other causes than the original cataract disease. For those afflicted with disease, clinically significant secondary cataracts can result in reduced visual acuity and increased glare in terms of color perception and contrast vision.

Secondary cataract is a common complication following extracapsular cataract extraction (ECCE) and subsequent implantation of an intraocular lens (IOL) into the capsular bag. The risk of secondary cataracts is even greatly increased if the IOL is not implanted in an empty capsular bag, because in this case the cells may migrate unimpeded to the posterior side of the capsular bag. Implantation of artificial capsular bags also carries a relatively high risk of secondary cataracts or other complications caused by uncontrolled cell growth.

The incidence of secondary cataracts increases with time after surgery. Meta-analysis of cases of secondary cataracts of all prior types of IOLs showed an average increase of about 12% one year after surgery and an average increase of about 30% five years after surgery. Here, the age of the afflicted patient also appears to be a critical factor, and thus, it is unexpected that after a certain period of time, almost all children and adolescents undergoing treatment may suffer from postoperative cataract.

Heretofore, it has not been possible to quantitatively clear all epithelial cells during ocular surgery without the use of toxic drugs that could damage the endothelial cell layer of the cornea or other ocular tissue. Vision problems caused by fibrosis and PCO are treated in part by the so-called focal Nd: YAG capsulotomy. However, particularly fibrous texture may still impair the function of the implant (e.g., an accommodating IOL).

Thus, to date, effective and long-term preventative measures against secondary cataracts and other medical complications that occur in connection with the implantation of ophthalmic implants have not been achieved.

Disclosure of Invention

It is an object of the present invention to reduce the risk of PCO and fibrosis for a therapeutic method of implanting an ophthalmic implant in a human or animal patient. It is a further object of the present invention to provide an ophthalmic implant system for such a method of treatment that can reduce the risk of PCO and fibrosis.

According to the invention, these objects are achieved by a tissue adhesive for use in a method of treatment for implantation of an ophthalmic implant in a human or animal patient, as described in claim 1, and by an ophthalmic implantation system, as described in claim 8. Advantageous embodiments having advantageous configurations of the invention are specified in the respective dependent claims; advantageous embodiments of each aspect of the invention are to be considered as advantageous embodiments of the corresponding other aspects of the invention.

A first aspect of the invention relates to a tissue adhesive for use in a method of treatment in which an ophthalmic implant is implanted in a human or animal patient and the ophthalmic implant is at least partially cohesively bonded to tissue of the patient's eye by the tissue adhesive in other words, the invention provides a tissue adhesive which is useful for partially or fully cohesively bonding the ophthalmic implant to the patient's capsular bag during a method of treatment in which, for example, the patient's ocular lens is replaced by the ophthalmic implant. Correspondingly, tissue adhesives may be used to cohesively adhere artificial capsular bags to patient's ocular tissue, as well as for other types of ocular implants. In the context of the present invention, tissue adhesive is understood to mean a pharmacologically tolerable adhesive designed to form an in vivo cohesive bond between biological ocular tissue and an ophthalmic implant adjoining the ocular tissue in question. Thus, tissue adhesives in the context of the present disclosure are not direct adhesion promoters (e.g., such as fibronectin, vitronectin, laminin, or glycoproteins), but rather create cohesive bonds between the ocular tissue in question and the implant under chemical curing. Tissue adhesives are known per se for different surgical methods for wound closure without using surgical suture material, but have not been described so far for the medical indications of the invention in the context of general eye surgery. By means of the tissue adhesive according to the invention, the ophthalmic implant can be fixed and firmly integrated in the eye without damaging the eye tissue. Thus, problems commonly occurring in general treatment methods, such as dislocation, tilting, rotation, or detachment of the implant, can be reliably prevented. Furthermore, such capsular bag-based implants to date may be associated with Posterior Capsular Opacification (PCO) and fibrosis, which may be caused inter alia by residual lens epithelial cells. In contrast, the possibility of cohesively bonding the implant to the ocular tissue by means of a tissue adhesive can reliably prevent the implant from being destroyed by lens epithelial cells or the like. Thus, any lens epithelial cells and other cell types that remain in the eye during surgery no longer cause PCO and fibrosis or similar complications that can impair vision and the functionality of the implant (e.g., an intraocular lens (IOL), particularly an accommodating IOL, or an artificial capsular bag). In general, in the context of the present disclosure, "a" is to be understood as an indefinite article, i.e., if there is no explicit indication to the contrary, "at least one". Conversely, "a" or "an" may also be understood as "only one". In the context of the present disclosure, the word "comprising" should generally be construed such that the corresponding feature is present, but the presence of other features is not excluded. Conversely, in the context of this disclosure, the word "comprising" may be alternatively interpreted as meaning "consisting of" or "consisting essentially of" meaning that, apart from the features mentioned after the word in this form, no further features ("consisting of") or certain further features may be present, i.e. those features that do not significantly alter the essential features of the inventive subject matter ("consisting essentially of").

In an advantageous configuration of the invention, the tissue adhesive is provided as a composition with an active ingredient release system designed to: in the implanted state of the tissue adhesive, at least one active pharmacological ingredient is preferably released in a controlled manner and/or the tissue adhesive is provided as a composition with the active pharmacological ingredient immobilized on the tissue adhesive. In this way, tissue adhesives may advantageously be used after implantation for local release of one or more pharmacologically active substances, or for long-term positioning of the active ingredient at a desired location. In this way, one or more active ingredients can be released (preferably in a controlled manner), in particular into the area in which they are desired. Systemic or non-specific administration of the active ingredient and associated side effects can advantageously be avoided. For example, the active ingredient thapsigargin can damage the epithelial cell layer of the cornea when released freely into the aqueous humor in the anterior chamber. In contrast, preferably controlled release into the immediately adjacent tissue ensures that the pharmacological effect is limited to the desired site. Furthermore, the amount of active ingredient can be reduced to the amount required for treatment, which means that, despite improved and long-term efficacy, a reduced risk of complications and considerable cost savings can be achieved.

A further benefit results from the at least one active ingredient being designed to promote and/or inhibit at least one aspect from the group comprising: proliferation, migration and differentiation of cells occurs in the human or animal eye. In other words, the active ingredient is designed to control the occurrence of PCO or fibrosis by specifically promoting and/or inhibiting proliferation, migration and/or differentiation of cells (e.g., lens epithelial cells in the implanted state). The inhibition of transformation, cell growth and/or cell division of such cells also advantageously prevents destruction or overgrowth of implants "fixed" in ocular tissue by tissue adhesives, which can be particularly effective in inhibiting and preventing the occurrence of PCO or fibrosis and related complications. Alternatively or additionally, it may be the case that proliferation, migration and/or differentiation of cells (e.g. lens epithelial cells) is specifically promoted. This results in improved tissue growth by active cell culture and thus promotes natural wound healing. Thus, the proliferation and migration of cells occurring in the eyes of humans or animals can be controlled such that these cells can no longer cause the above-mentioned problems leading to, for example, PCO. Furthermore, the induction and possible control of rapid fibrosis is advantageous because it increases the stability of the implant, rapidly ensures the final positioning of the implant in the ocular tissue, and shortens the healing time (for example after cataract surgery or after insertion of an artificial capsular bag). In principle, the cells can also be present in various cell forms, for example as fibroblasts and/or as cell aggregates, for example as Wedl cells.

In a further advantageous configuration, the at least one active ingredient is selected from the group comprising: 5-fluorouracil; thapsigargin; paclitaxel; growth factors, in particular tgfβ; and an angiogenesis inhibitor; and derivatives, especially (meth) acrylate modified derivatives and isomers; and any mixtures thereof. 5-fluorouracil is a cytostatic agent and belongs to the group of antimetabolites as pyrimidine analogs. It has structural similarity to pyrimidinyl uracils and is incorporated into RNA at its position. Furthermore, 5-fluorouracil inhibits a key enzyme for pyrimidine biosynthesis: thymidylate synthase (thymidilate synthase). Furthermore, the active ingredient provided may be a cytotoxin modified or unmodified thapsigargin. Thapsigargin is an inhibitor of the calcium atpase inhibitor of the endoplasmic reticulum, which greatly reduces cell growth in the capsular bag at low concentrations (100 nM) and induces cell death at higher concentrations (10-100 μm). Preferably, the thapsigargin is (meth) acrylate modified in order to ensure sterically unhindered covalent bonding with the double bond. Thapsigargin can be correspondingly derivatized (e.g., by reaction with (meth) acrylic anhydride). In the context of the present disclosure, the term "(meth) acrylate" is understood to mean both acrylate and methacrylate and mixtures thereof. Paclitaxel is a spindle toxin and inhibits the degradation of spindle filaments formed from tubulin (microtubuli) by binding to β -tubulin. This blocks mitotic cell division in G2 and M phases, so that there is no cell proliferation. Thus, the compounds mentioned and isomers and/or derivatives thereof may be used, alone or in any combination, in particular, to inhibit proliferation, migration and differentiation of cells occurring in the human or animal eye. Alternatively or additionally, one or more growth factors may be provided to promote a wound healing response. For example, the growth factor may be or comprise TGF-beta (TGF-beta 1, TGF-beta 2, TGF-beta 3). Furthermore, the active ingredient provided may be one or more angiogenesis inhibitors. The angiogenesis inhibitor may be selected from the group comprising: VEGF inhibitors, VEGFR inhibitors, antibodies, fab fragments, single chain variable fragments (scFv), multivalent antibody fragments (scFv multimers), peptide aptamers, and peptides. VEGF inhibitors are a group of structurally diverse drugs that bind to VEGF growth factors and thus inhibit angiogenesis. In contrast, VEGFR inhibitors are drugs that bind to the VEGF receptor (VEGFR). These may be small molecules from the group of Tyrosine Kinase Inhibitors (TKIs) or antibodies, in particular monoclonal antibodies. In both cases, there is an interruption of the intracellular signaling cascade, which results in inhibition of angiogenesis. Alternatively or additionally, fab fragments, single chain variable fragments (scFv), multivalent antibody fragments (scFv multimers), peptide aptamers, and peptides may be provided that prevent, or at least significantly slow, angiogenesis. Thus, a choice may be made to optimize according to the respective clinical conditions. Antibody fragments offer the advantage of having high binding affinity/avidity and specificity for a wide range of biological target structures and haptens. Furthermore, single-stranded fragments may be cross-linked or expressed as diabodies (60 kDa), triabodies (90 kDa), tetrabodies (120 kDa), etc., wherein there may be a difference in linker length between the V domains. Moreover, a particular advantage is that 60-120kDa molecules increase cell penetration and have a faster clearance compared to the corresponding Ig (150 kDa). Furthermore, it may be the case that the antibody is a diabody, a triabody, a tetrabody, a penta-chain antibody, a hexa-chain antibody, a hepta-chain antibody or an octa-chain antibody. In other words, the antibody is monospecific, bispecific, trispecific, tetraspecific, penta-specific, hexa-specific, hepta-specific, octa-specific, non-specific or multispecific. This allows two, three, four, five, six, seven or eight target structures or target proteins to be cross-linked, potentially allowing scFv multimers to match particularly precisely and individually the possibly patient-specific spatial arrangement of target epitopes in order to prevent angiogenesis. The increased binding valency of scFv multimers results in particularly high avidity. The at least one angiogenesis inhibitor may be chosen in particular from the group comprising: bevacizumab, ibuprofen, ranibizumab, ramucirumab, aflibercept, pegatanib, thalidomide, axitinib, lenvatinib, duritinib, mo Tisha, pazopanib, regorafenib, sorafenib, sunitinib, tivozanib, vanadinib, and biological analogs thereof. In this way, tyrosine kinases can be specifically inhibited, and some of the compounds mentioned (as multi-kinase inhibitors) are capable of inhibiting a variety of protein kinases of various classes and thus have improved efficacy.

Further benefits come from the covalent attachment of the active ingredient to the tissue adhesive, especially via (meth) acrylate groups, and/or from the active ingredient and the tissue adhesive being in the form of an interpenetrating network. Covalent bonding (optionally in the case of (meth) acrylates or spacers) allows particularly simple and flexible immobilization of the active ingredient on the tissue adhesive without steric hindrance. Furthermore, depending on the respective configuration form, the (meth) acrylate or spacer may provide the necessary functional groups in order to enable covalent binding of the active ingredient to the tissue adhesive. In some embodiments, this may also be achieved, for example, by graft polymerization. In general, other fixation techniques may also be provided, such as, for example, interpenetrating or semi/pseudo interpenetrating networks, etc.

In a further advantageous configuration of the invention, the tissue adhesive is in the form of a hydrogel and/or an interpenetrating network and/or a semi-interpenetrating network in the uncured state. Alternatively or additionally, the tissue adhesive is capable of curing by at least one mechanism from the group of: anaerobic curing, UV light curing, anionic curing, activator curing, moisture curing and thermal curing. In this way, the mode and initiation of curing to the corresponding end use can be optimized. UV initiated curing is preferred.

Further benefits result from the tissue adhesive comprising: merro (methacrylated recombinant tropoelastin) prepolymer; and/or GelMA (methacrylated gelatin)/HA-NB (N- (2-aminoethyl) -4- (4- (hydroxymethyl) -2-methoxy-5-nitrosophenoxy) butanamide). This achieves a highly elastic, strongly adherent and biocompatible tissue adhesive with good adhesion to the soft tissue of the capsular bag. The preparation of suitable merro prepolymers is common general knowledge, e.g., according to Annabi et al ("Engineering a highly elastic human protein-based sealant for surgical applications [ engineering of high elasticity human protein based sealants for surgical applications ]]"Sci.Transl.Med. [ science. Conversion medicine ]]9, eaai7466 (2017)). Recombinant human tropoelastin and methacrylic anhydride can be used to synthesize merro prepolymers. For example, the merro prepolymers can be synthesized using 8%, 15% and 20% (v/v) methacrylic anhydride at 54% (low), 76% (medium) and 82% (high) methacryloyl substitution levels, respectively. In principle, different weight or volume ratios are also possible. Then it was possible to obtain a film by irradiation with UV light (6.9 mW/cm ² The method comprises the steps of carrying out a first treatment on the surface of the 360nm to 480 nm) are photocrosslinked at different exposure times of 30s to 180s to cure the formed merro hydrogels. The photoinitiator used may be, for example, [ 2-hydroxy-1- (4- (hydroxyethoxy) phenyl) -2-methyl-1-propanone (Irgacure 2959); 0.5%, w/v]. Alternatively or additionally, the tissue adhesive may comprise or consist of: a polymer comprising GelMA (methacrylated gelatin)/NB (N- (2-aminoethyl) -4- (4- (hydroxymethyl) -2-methoxy-5-nitrosophenoxy) butyramide). This is a photopolymer that mimics the composition of the extracellular matrix (ECM). This matrix hydrogel, which is also based on biomacromolecules, can be cured rapidly after UV light irradiation in order to bond the implant to the capsular bag. The polymer may additionally be combined with a hydrophilic polymer, preferably selected from the group comprising: alginic acid, carboxymethyl cellulose, chitosan, dextran sulfate, pentosan polysulfate, carrageenan, pectin derivatives, cellulose derivatives, glycosaminoglycans (especially hyaluronic acid, dermatan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, heparin, heparan sulfate, hyaluronic acid), agarose, starch, methylcellulose, polymannuronate, polyguluronic acid, amylose, amylopectin, callose, polygalactomannan, xanthan gum, poly (ethylene oxide), poly (ethylene glycol), collagen, gelatin, fibrin, fibrinogen, fibronectin, vitronectin, poly (ethylene oxide), poly (acrylic acid), poly (methacrylic acid), poly (acrylamide), polyvinylpyrrolidone, poly (amino acid), poly (amine), poly (imine), mixtures thereof and/or copolymers thereof and/or pharmaceutically acceptable salts thereof. For example, the hydrophilic polymer may be Hyaluronic Acid (HA). Suitable tissue adhesives and their production are known, for example, from Hong, y., zhou, f., hua, y., et al (A strongly adhesive hemostatic hydrogel for the repair ofarterial and heart bleeds. [ strongly adhesive hemostatic hydrogels for repairing arterial and cardiac hemorrhages]Nat Commun [ Nature communication 10,2060 (2019)) (see pages 7-9, methods). For example, the tissue adhesive may comprise: 1% -10%, in particular 5%, of a methacrylated gelatin (GelMA); and 0.5% -3%, in particular 1.25% of N- (2-aminoethyl) -4- (4- (hydroxymethyl) -2-methoxy-5-ylideneNitrophenoxy) Butyramide (NB), wherein NB binds HA through LAP (HA-NB). In general, unless otherwise indicated, the percentage figures in the context of the present disclosure should be considered as mass percentages.

A second aspect of the invention relates to an implant system that can reduce the risk of PCO and fibrosis, wherein the implant system comprises: an ophthalmic implant for implantation in a human or animal eye, and a tissue adhesive by which the ophthalmic implant can be at least partially cohesively bonded to the eye tissue of a patient. With the implant system of the present invention, the ophthalmic implant can be fixed and firmly incorporated into ocular tissue (e.g., capsular bag) without damaging the tissue. Thus, problems commonly occurring in the corresponding treatment methods, such as dislocation, tilting, rotation, or detachment of the implant, can be reliably prevented. Furthermore, in the case of cataract surgery, such capsular bag-based implants are used in association with Posterior Capsular Opacification (PCO) and fibrosis, which may be caused inter alia by residual lens epithelial cells in the equatorial region of the capsular bag. In contrast, the possibility of cohesively bonding the implant to the capsular bag by means of a tissue adhesive may reliably prevent the implant from being damaged by lens epithelial cells or the like. Thus, any remaining lens epithelial cells of the capsular bag that are ready for implantation will no longer cause PCO and fibrosis that can impair vision and implant functionality. In certain embodiments, the implant has a body with at least one haptic section and at least one optic section, wherein the tissue adhesive may be placed on the haptic section alone, the optic section alone, or both sections. The tissue adhesive may in principle be present separately from the ophthalmic implant (e.g. in a separate package), or may have been applied to at least a portion of the implant. Further features and benefits thereof may be inferred from the description of the first aspect of the present invention.

In an advantageous configuration of the invention, the tissue adhesive and/or the ophthalmic implant designed according to the first aspect of the invention is an intraocular lens (IOL), in particular an accommodating IOL, or an artificial capsular bag. If the IOL is not implanted in an empty capsular bag, the risk of secondary cataract is actually increased, as in this case the cells may migrate unimpeded to the posterior or posterior surface of the capsular bag.

A further benefit results from the fact that the ophthalmic implant comprises a free amino group on its outer side via which the ophthalmic implant is cohesively bonded to the capsular bag by means of a tissue adhesive. In other words, the tissue adhesive and the implant are matched to each other such that the tissue adhesive having free amino groups can react and form covalent bonds at the surface of the implant in order to achieve high binding forces. For this purpose, the implant can consist at least on the surface of the corresponding polymer with free amino groups. Alternatively or additionally, the implant may have a coating providing free amino groups, such as a polyimide coating.

Further features of the invention will become apparent from the claims, the drawings and the description of the drawings. The features and feature combinations mentioned in the above description and those mentioned in the following description of the drawings and/or shown only in the drawings can be used not only in the respectively specified combinations but also in other combinations without departing from the scope of the invention. Accordingly, the invention should also be considered to include and disclose configurations of the invention which are not explicitly shown and described in the figures, but which result from the individual combinations of features from the described configurations and which can be created therewith. The disclosure should also be considered to extend to combinations of configurations and features, such that these configurations and combinations of features do not have all of the features of the independent claims as set forth in the initial wording. Furthermore, the disclosure should be considered to extend to combinations of configurations and features, especially via configurations set forth above, beyond or away from those set forth in the dependent references of the claims. The drawings show:

FIG. 1 is a reaction for forming a methacrylated gelatin (GelMA);

FIG. 2 cross-linking reaction of GelMA and modified hyaluronic acid (HA-NB) to produce a first network;

FIG. 3 is a second network created by cross-linking a first network;

FIG. 4 coupling reaction of thapsigargin with GelMA;

FIG. 5 coupling reaction of (meth) acrylate modified thapsigargin derivative with GelMA; and

fig. 6 is a basic diagram of an ophthalmic implant system of the present invention.

Detailed Description

Hong, y., zhou, f., huan, y, et al (A strongly adhesive hemostatic hydrogel for the repair ofarterial and heart bleeds [ strong adhesive hemostatic hydrogel for repair of arterial and cardiac hemorrhages ]. Nat com [ natural communication ]10,2060 (2019)) disclose a hydrogel tissue adhesive that resembles the composition of the extracellular matrix of biological connective tissue and is suitable for use in a treatment method in which the ocular lens of a human or animal patient is replaced by an ocular implant, and the ocular implant is cohesively bonded to the patient's capsular bag by the tissue adhesive. The treatment method may be, for example, cataract surgery. The tissue adhesive forms a hydrogel and consists of: about 5% of a methacrylated gelatin (GelMA); and about 1.25% N- (2-aminoethyl) -4- (4- (hydroxymethyl) -2-methoxy-5-Nitrosophenoxy) Butanamide (NB) (HA-NB) bound to glycosaminoglycan Hyaluronic Acid (HA). Fig. 1 shows a schematic of the reaction for forming GelMA, wherein gelatin is mixed with methacrylic anhydride and optionally maintained in DPBS (Dulbecco phosphate buffered saline) at 50 ℃ while stirring for 48 hours. The NB, in turn, binds with the HA and crosslinks with the GelMA to form a first GelMA/HA-NB network. The crosslinking reaction was started by UV photoactivation of the polymerization initiator lithium phenyl-2, 4, 6-trimethylbenzoyl-phosphinate (LAP) (0.1%). The cross-linking reaction of GelMA and modified hyaluronic acid (HA-NB) to produce the first network is schematically shown in fig. 2.

UV irradiation converts the hydroxymethyl groups of the NA to ketone groups, which react with the free amino groups of GelMA to form schiff bases, and thereby form a second network. The resulting second network is schematically shown in fig. 3. After UV photoactivation of LAP, the resulting tissue adhesive binds strongly to the moist biological tissue surface.

Cytotoxic thapsigargins (which are shown in fig. 4) are inhibitors of the calcium atpase inhibitor of the endoplasmic reticulum, which greatly reduce cell growth in the capsular bag at low concentrations (100 nM) and induce cell death at higher concentrations (10-100 μm). It is therefore in principle useful for preventing PCO and fibrosis. Free thapsigargin is released into aqueous humor in the anterior chamber, but can damage the epithelial cell layer of the cornea.

To prevent uncontrolled release of thapsigargin, according to fig. 4, the acrylate group of thapsigargin is covalently bound to GelMA. For this purpose, thapsigargin is added to the above-mentioned tissue adhesives, so that thapsigargin is covalently bound to GelMA, likewise by using UV and LAP for curing the tissue adhesives.

The bound thapsigargin cannot show any toxic effect because it must enter the cell in order to show toxicity. Aqueous humor contains matrix metalloproteinases whose concentration increases during cataract surgery due to elevated tgfβ levels. Matrix metalloproteinases are gelatinases that digest collagen and gelatin. In the presence of these matrix metalloproteinases, gelMA containing thapsigargin degrades over time, which may allow for controlled release of thapsigargin in an active ingredient release system. Due to incorporation into the tissue adhesive, small amounts of thapsigargin are released only in the vicinity of the tissue adhesive, and thus in the vicinity of the cells causing PCO and fibrosis, for a regulated period of time without damaging other tissues.

It should be emphasized that other active pharmacological ingredients may also be provided, which are incorporated into, covalently bound to, or in some other way form a composition with these or other suitable tissue adhesives. The composition may be formulated before, during and/or after final mixing of the tissue adhesive components and curing by LAP/UV. The one or more active ingredients need not be bound to the acryl groups of the tissue adhesive; alternatively or additionally, a bond to the free amino group of GelMA may also be provided.

Fig. 5 shows a schematic coupling of modified thapsigargin with GelMA. In this case, thapsigargin is covalently bound to GelMA or to tissue adhesive 14 via acrylate groups. This has the following benefits: lower steric hindrance; and correspondingly simpler reaction mechanisms with higher and faster conversion. For this purpose, thapsigargin was first derivatized with methacrylic anhydride in phosphate buffered saline (DPBS-Dulbecco phosphate buffered saline) at about 50℃for up to 48 hours. The methacrylate groups are here bound to the free OH groups of thapsigargin. Subsequently, the derivatized thapsigargin is covalently bound via the methacrylate groups to the corresponding methacrylate groups in the modified gelatin (GelMA). After ocular surgery and implantation of implant 12, degradation by Matrix Metalloproteinases (MMPs) has been described as resulting in slow release of thapsigargin in the surgical field.

Fig. 6 shows a basic view of the ophthalmic implant system 10 of the present invention. The implant system 10 includes an ophthalmic implant 12 by which the lens of a patient's eye can be replaced. Implant 12 may be in the form of, for example, an accommodating intraocular lens. Alternatively, the implant 12 may also be a different type of implant, such as a non-accommodating IOL, an (optionally accommodating) IOL having one or more haptics, or an artificial capsular bag (not shown). Suitable artificial capsular bags (into which the IOL may then be implanted) are known, for example, from US 8,900,300 B1. In addition, the implant system 10 includes a tissue adhesive 14 by which the ophthalmic implant 12 is cohesively bonded to the patient's capsular bag after implantation thereof. The tissue adhesive 14 may be in the form described above and stored in a suitable package 16 prior to use. Alternatively, the tissue adhesive 14 may have been applied to the implant 12. In this case, the implant 12 and tissue adhesive 14 are preferably stored so as to prevent premature curing of the tissue adhesive 14, i.e., during storage or prior to implantation.

Parameter values specified in the literature for defining processes and measurement conditions for characterizing specific properties of the subject matter of the invention are also to be considered as covered within the scope of the invention in case of deviations due to e.g. measurement errors, systematic errors, weighing errors, etc.

List of reference symbols

10. Implant system

12. Implant

14. Tissue adhesives

16. Packaging arrangement

Claims

1. A tissue adhesive (14) for use in a method of treatment in which an ophthalmic implant (12) is implanted in a human or animal patient and the ophthalmic implant (12) is at least partially cohesively bonded to tissue of an eye of the patient by the tissue adhesive (14), characterized in that the tissue adhesive (14) is in the form of an interpenetrating network and/or a semi-interpenetrating network in an uncured state.

2. The tissue adhesive (14) of claim 1,

it is characterized in that the method comprises the steps of,

the tissue adhesive is provided as a composition having an active ingredient release system designed to: in the implanted state of the tissue adhesive (14), at least one active pharmacological ingredient is preferably released in a controlled manner and/or in that the tissue adhesive (14) is provided as a composition with an active pharmacological ingredient fixed on the tissue adhesive (14).

3. The tissue adhesive (14) according to claim 2,

it is characterized in that the method comprises the steps of,

the at least one active ingredient is designed to promote and/or inhibit at least one aspect from the group comprising: proliferation, migration and differentiation of cells occurs in the human or animal eye.

4. The tissue adhesive (14) according to claim 3,

it is characterized in that the method comprises the steps of,

the at least one ingredient is selected from the group comprising: 5-fluorouracil; thapsigargin; paclitaxel; growth factors, in particular tgfβ; and an angiogenesis inhibitor; and derivatives, especially (meth) acrylate modified derivatives and isomers; and any mixtures thereof.

5. The tissue adhesive (14) according to claim 2 to 4,

it is characterized in that the method comprises the steps of,

the active ingredient is covalently bound to the tissue adhesive (14), in particular via (meth) acrylate groups, and/or in that the active ingredient and the tissue adhesive (14) are in the form of an interpenetrating network.

6. The tissue adhesive (14) according to claim 1 to 5,

it is characterized in that the method comprises the steps of,

in the uncured state, the tissue adhesive is in the form of a hydrogel and/or interpenetrating network and/or semi-interpenetrating network and/or is capable of curing by at least one mechanism from the group of: anaerobic curing, UV light curing, anionic curing, activator curing, moisture curing and thermal curing.

7. The tissue adhesive (14) according to claim 1 to 6,

it is characterized in that the method comprises the steps of,

the tissue adhesive comprises: merro (methacrylated recombinant tropoelastin) prepolymer; and/or polymers containing GelMA (methacrylated gelatin)/NB (N- (2-aminoethyl) -4- (4- (hydroxymethyl) -2-methoxy-5-nitrosophenoxy) butyramide) preferably in combination with a biopolymer, in particular Hyaluronic Acid (HA).

8. An ophthalmic implant system (10), the ophthalmic implant system comprising: an ophthalmic implant (12) for implantation in a human or animal eye, and a tissue adhesive (14) by which the ophthalmic implant (12) is at least partially cohesively bondable to eye tissue of the patient.

9. The ophthalmic implant system (10) of claim 8,

it is characterized in that the method comprises the steps of,

the tissue adhesive (14) according to any one of claims 1 to 8, and/or in that the ophthalmic implant (12) is an intraocular lens or an artificial capsular bag.

10. An ophthalmic implant system (10) according to claim 8 or 9,

it is characterized in that the method comprises the steps of,

the ophthalmic implant (12) comprises a free amino group on its outer side, via which free amino group the ophthalmic implant (12) is cohesively bonded to the eye tissue by the tissue adhesive (14).